title: Pipoxolan ameliorates cerebral ischemia via inhibition of neuronal apoptosis and intimal hyperplasia through attenuation of VSMC migration and modulation of matrix metalloproteinase-2/9 and Ras/MEK/ERK signaling pathways.
abstract: Pipoxolan (PIPO) has anti-spasmodic effects, and it is used clinically to relieve smooth muscle spasms. Cerebrovascular disease is one of the leading causes of disability and death worldwide. The main aim of this study was to investigate the effects of PIPO on cerebral ischemia and vascular smooth muscle cell (VSMC) migration in vivo and in vitro. Cerebral infarction area, ratio of intima to media area (I/M ratio) and PCNA antibody staining of the carotid artery in vivo were measured. Cell viability of A7r5 cells, PDGF-BB-stimulated cell migration, and potential mechanisms of PIPO were evaluated by wound healing, transwell and Western blotting. PIPO (10 and 30 mg/kg p.o.) reduced: the cerebral infarction area; neurological deficit; TUNEL-positive cells; cleaved caspase 3-positive cells; intimal hyperplasia; and inhibited proliferating cell nuclear antigen (PCNA)-positive cells in rodents. PIPO (5, 10 and 15 µM) significantly inhibited PDGF-BB-stimulated VSMC migration and reduced Ras, MEK, and p-ERK levels. Moreover, PIPO decreased levels of matrix metalloproteinases -2 and -9 in PDGF-BB-stimulated A7r5 cells. In summary, PIPO is protective in models of ischemia/reperfusion-induced cerebral infarction, carotid artery ligation-induced intimal hyperplasia and VSMC migration both in vivo and in vitro. PIPO could be potentially efficacious in preventing cerebrovascular and vascular diseases.
authors.affiliation: Department of Pharmacology, College of Medicine, China Medical University, Taichung, Taiwan ; Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yuh-Fung
authors.initials: YF
authors.lastname: Chen
authors.forename: Huei-Yann
authors.initials: HY
authors.lastname: Tsai
authors.forename: Kuo-Jen
authors.initials: KJ
authors.lastname: Wu
authors.forename: Lian-Ru
authors.initials: LR
authors.lastname: Siao
authors.forename: W Gibson
authors.initials: WG
authors.lastname: Wood
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D062186:Arterial Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004148:Dioxolanes / Q000494:pharmacology*; D006965:Hyperplasia / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008813:Mice, Inbred ICR; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism
chemical_list: D004148:Dioxolanes; D018809:Proliferating Cell Nuclear Antigen; C000121:pipoxolan; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016283:Proto-Oncogene Proteins p21(ras)